Lung cancer is the leading cause of cancer deaths worldwide. More than 85% of lung cancers are classified as non-small cell lung cancer (NSCLC), which is defined by pathological characteristics. Oncogenic mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain are found in a significant portion of NSCLC. Such mutations, which present most commonly as small in-frame deletions in exon 19 or as point mutations in exon 21, confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and have enabled molecularly targeted therapy in this malignancy. By analyzing the tumors of patients with lung adenocarcinoma, we have identified two novel EGFR genomic alterations that have not previously been reported in lung cancer: EGFR kinase domain duplication (EGFR- KDD) and EGFR-RAD51 fusion. The objective of this proposal is to understand the role of these newly discovered EGFR alterations in lung cancer. The EGFR-KDD is an intragenic rearrangement resulting in the tandem duplication of exons 18-25, the exons that encode the entire EGFR kinase domain. EGFR-RAD51 is the result of a chromosomal translocation encompassing EGFR exons 1-24, which includes all functional domains of EGFR except the C-terminal regulatory region, and RAD51 exons 4-10, which includes the ATPase and oligomerization domains, but not the DNA binding N-terminus. Based on our preliminary data, we hypothesize that EGFR rearrangements, specifically the EGFR-KDD and EGFR-RAD51, are recurrent, oncogenic, and therapeutically targetable alterations in lung cancer. To test this hypothesis, we will carry out experiments to 1) identify the best strateg to therapeutically inhibit EGFR-KDD; to 2) determine whether EGFR-RAD51 is oncogenic and sensitive to EGFR-targeted agents; and to 3) determine the frequency of EGFR-KDD and EGFR-RAD51 in non-small cell lung cancer. Collectively, the proposed research uses in vitro and in vivo models as well as patient-derived data to address a previously unrecognized potential mechanism of oncogenesis in lung cancer: EGFR rearrangements. Importantly, understanding the consequences of these EGFR alterations may provide insights into EGFR biology and reveal new uses for FDA approved agents. As such, these studies are expected to have rapid translation into the clinic. Finally, as a physician-scientist-in-training who aims to have a career as a translational cancer researcher, the proposed studies provide an exciting and fertile training avenue.